Gene find offers hope to breast cancer victims

A "gang of four" genes is responsible for the lethal spread of breast cancer, according to a study published today that provides new insight into how to treat the disease more effectively.

Along with a second study published today which reveals the patients most likely to benefit from low doses of chemotherapy, and thus be spared side effects, the work provides a vivid glimpse of the huge impact that genetics will make on cancer treatment.

The studies point to a future where patients are subjected to tumour gene tests to make chemotherapy more effective and less of an ordeal. It also offers the hope of treatments that can curb the spread of the disease throughout the body, the cause of most cancer deaths.

A team in New York with researchers now working at the Hospital Clinic de Barcelona and the Institute for Research in Biomedecine in Spain, reports in the journal Nature a set of four key genes in human breast cancer cells that play a role in metastasis, the spread of the cancer, to the lungs.

A number of genes are already known to contribute to the spread to the lungs. But Prof Joan Massagué and colleagues at Memorial Sloan Kettering Cancer Centre, New York, now show how four co-operate to promote the formation of new tumour blood vessels, the release of cancer cells into the bloodstream, and the penetration of tumour cells from the bloodstream into the lung.

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The gene set comprises EREG, MMP1, MMP2 and Cox2 and the abnormal activation of all four enables the breast cancer to invade the lungs. Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four had a dramatic effect.

Prof Massagué said: "The remarkable thing was that while silencing these genes individually was effective, silencing the quartet nearly completely eliminated tumour growth and spread."

In experiments on human breast tumours implanted in mice, the researchers also found that they could reduce the growth and spread of the disease by simultaneously targeting two of the proteins produced by these genes, using drugs already on the market. "We found that the combination of these two inhibitory drugs was effective, even though the drugs individually were not very effective," said Prof Massagué. "This really nailed the case that if we can inactivate these genes in concert, it will affect metastasis."

The researchers now want to test combination therapy with the drugs - cetuximab (trade name Erbitux) and celecoxib (Celebrex) - to treat breast cancer metastasis.

The other two genes are matrix metalloproteinases (MMP1 and MMP2) that participate in the formation of new blood vessels. Although there are efforts to find drugs to inhibit them, none is in clinical use "owing to toxicities due to the large number of MMPs that function normally in our bodies and that the existing inhibitors may be acting on", said Prof Massagué.

His team is now studying the genes that enable breast cancer to spread to other parts of the body, such as the bone.

A second study published in Nature, shows that scientists in Texas have isolated 87 genes that seem to affect how sensitive human cancer cells are to certain chemotherapy drugs.

The study highlights a new way to screen for alterations in cancer cells that make them specifically sensitive to treatments, so that they may leave normal tissue relatively unharmed.